Bladder cancer accounts for approximately 2% of all malignant cancers and is the fifth and tenth most common cancer in men and women, respectively. The American Cancer Society estimated that 54,500 new cases and 11,700 deaths would have occurred in 1997. Superficial bladder cancers (pTa, pT1 and CIS) account for 70-80% of cancers at first presentation. Management of superficial bladder cancer may be achieved by endoscopic surgical resection often followed by a course of adjuvant intravesical chemotherapy or immunotherapy with the aim of both eradicating remaining tumor cells and preventing tumor recurrence (Herr H W (1987) Intravesical therapy—a critical review. Urol Clin N Am 14:399-404). Both anti-neoplastics (Mitomycin C [MMC], epirubicin and thioTEPA) and immunotherapy (BCG) administered intravesically are effective at reducing tumor recurrence rates although it is unclear whether disease progression to muscle invasive tumors is prevented (Newling D (1990) Intravesical therapy in the management of superficial transitional cell carcinoma of the bladder: the experience of the EORTC GU group, Br J Cancer 61:497-499; Oosterlink et al. (1993) A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 149:749-752). This observation in conjunction with the fact that mortality from bladder cancer is still high underscores the need to develop more effective therapeutic agents (Oosterlink et al. 1993).
One such therapeutic agent is MMC which belongs to a class of compounds known as bioreductive drugs (Workman 1994). MMC represents one of the antineoplastic agents used to treat superficial bladder cancers (Maffezzini et al, 1996, Tolley et al, 1996). MMC is activated to a cytotoxic species by cellular reductases although the role of specific reductase enzymes involved in bioreductive activation remains poorly defined and controversial (Cummings et al, 1998a). This is particularly true for the enzyme NQO1 (NAD(P)H:Quinone oxidoreductase, EC 1.6.99.2) which is a cytosolic flavoprotein which catalyses the two electron reduction of various quinone based compounds using either NADH or NADPH as electron donors (Schlager and Powis, 1988, Siegel et al, 1990). The structurally related compound 5-(1-aziridinyl)-3-(hydroxymethyl)-2-[(E)-3-hydroxyprop-1-enyl]-1-methyl-1H-indole-4,7-dione (EO9) is however a much better substrate for NQO1 than MMC (Walton et al, 1991) and a good correlation exists between NQO1 activity and chemosensitivity in vitro under aerobic conditions (Robertson et al, 1994, Fitzsimmons et al, 1996, Smitkamp-Wilms et al, 1994). Under hypoxic conditions however, EO9's properties are markedly different with little or no potentiation of EO9 toxicity observed in NQO1 rich cells (Plumb and Workman, 1994). In NQO1 deficient cell lines however, large hypoxic cytotoxicity ratios have been reported (Workman, 1994). Therefore, EO9 has the potential to exploit the aerobic fraction of NQO1 rich tumors or the hypoxic fraction of NQO1 deficient tumors (Workman, 1994).
EO9 has been clinically evaluated but despite reports of three partial remissions in phase I clinical trials, no activity was seen against NSCLC, gastric, breast, pancreatic and colon cancers in subsequent phase II trials (Schellens et al, 1994, Dirix et al, 1996). These findings are particularly disappointing in view of the preclinical studies (Hendriks et al, 1993) together with reports that several tumor types have elevated NQ01 levels (Malkinson et al, 1992, Smitkamp-Wilms et al, 1995, Siegel et al, 1998). Several possible explanations have been proposed to explain EO9's lack of clinical efficacy (Connors, 1996, Phillips et al, 1998). Recent studies have demonstrated that the failure of EO9 in the clinic may not be due to poor pharmacodynamic interactions but may be the result of poor drug delivery to tumors (Phillips et al, 1998). The rapid plasma elimination of EO9 (tl/z=10 min in humans) in conjunction with poor penetration through multicell layers suggests that EO9 will not penetrate more than a few microns from a blood vessel within its pharmacokinetic lifespan (Schellens et al, 1994, Phillips et al, 1998). Intratumoural administration of EO9 to NQ01 rich and deficient tumors produced significant growth delays (although a distinction between damage to the aerobic or hypoxic fraction was not determined) suggesting that if EO9 can be delivered to tumors, therapeutic effects may be achieved (Cummings et al, 1998b). While these undesirable characteristics are a serious setback for the treatment of systemic disease, paradoxically they may be advantageous for treating cancers which arise in a third compartment such as superficial bladder cancer. In this scenario, drug delivery is not problematical via the intravesical route and the penetration of EO9 into avascular tissue can be increased by maintenance of therapeutically relevant drug concentrations within the bladder (using a one hour instillation period for example). While this method of instilling EO9 within the bladder may be useful, there still remains a need for drug delivery vehicles that are capable of delivering an effective amount of EO9 within the bladder.